title: Pro-soft Val-boroPro: a strategy for enhancing in vivo performance of boronic acid inhibitors of serine proteases.
abstract: Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at physiological pH, which attenuates its inhibitory potency >100-fold, which is a "soft drug" effect. Here we show that this phenomenon can be exploited to create prodrugs with unique properties and potential for selective in vivo targeting. Enzyme-mediated release delivers 1 to the target in the active form at physiological pH; cyclization attenuates systemic pharmacological effects from subsequent diffusion. This "pro-soft" design is demonstrated with a construct activated by and targeted to DPPIV, including in vivo results showing improved antihyperglycemic activity and reduced toxicity relative to 1. Pro-soft derivatives of 1 can help to illuminate the mechanisms underlying the three biological activities, or to help localize 1 at a tumor and thereby lead to improved anticancer agents with reduced toxicity. The design concept can also be applied to a variety of other boronic acid inhibitors.
authors.affiliation: Tufts University Sackler School of Graduate Biomedical Sciences, Department of Biochemistry, 136 Harrison Avenue, Boston, Massachusetts 02111, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Poplawski
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.forename: David G
authors.initials: DG
authors.lastname: Sanford
authors.forename: James L
authors.initials: JL
authors.lastname: Sudmeier
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003500:Cyclization; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D001897:Boronic Acids; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C477478:PT-100 dipeptide; D011355:Prodrugs; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases; D018819:Dipeptidyl Peptidase 4